Diabetes is a chronic disease characterized by the presence of hyperglycaemia that is triggered when the body loses its ability to produce enough insulin or to use it effectively. There are two main types of diabetes: type 1 and type 2. Type 2 diabetes is the most common type of diabetes which usually occurs in adults, but there are increasingly more cases of children and teenagers.
The number of people with type 2 diabetes is rapidly increasing worldwide. This increase is associated with the economic development, which implies an increased aged population and changes in lifestyle (unhealthy diets and reduced physical activity).
Diabetes can cause serious late complications which are classified in microangiopathic (retinopathy, neuropathy and diabetic nephropathy) and macroangiopathic (cardiovascular disease).
Diabetic retinopathy (DR) is the most common complication of diabetes and the leading cause of decreased visual acuity and blindness in working-age population in developed countries. The incidence of DR increases with the time of evolution of diabetes. Thus, 90% of patients with type 1 diabetes and 60% of patients with type 2 diabetes have some degree of DR after 20 years of evolution of diabetes. The prevalence of DR in Western countries is very similar and is around 30% and in 10% of cases the DR is in advanced stages that seriously threaten vision, as described in Yau et al., Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy, Diabetes Care, 2012, 35, 556-64.
According to the International Diabetes Federation. Diabetes Atlas (6th Edition, 2014) (http://www.idf.org/diabetesatlas), the number of diabetic patients in the world will exponentially grow in the coming years: it is estimated that will rise from 387 million of diabetic patients in 2014 to 592,000,000 in 2035. Consequently, the number of patients with DR will also increase in parallel.
A strict control of blood glucose and blood pressure are essential for preventing or slowing the progression of DR. However, the therapeutic objectives are difficult to achieve and consequently, the DR is eventually developed in a high proportion of patients.
Current treatments for DR such as laser photocoagulation, intravitreal injections of corticosteroids or blocking agents of vascular endothelial growth factor (anti-VEGF: ranibizumab, bevacizumab, pegaptanib, and aflibercept) or vitreoretinal surgery are indicated in very advanced stages of the disease, have limited effectiveness and are associated with significant adverse effects. Thus, the laser treatment is associated with a moderate vision loss, a reduced field of view, a reduced colour vision, and a reduction in contrast sensitivity. Intravitreal injections involve adverse effects such as infections, glaucoma and cataract formation and, since they must be repeatedly administered, the risk of occurrence of side effects is multiplied. In addition to the adverse local effects, anti-VEGF agents can also cause systemic complications due to its ability to pass into the systemic circulation. In short, current treatments for DR are only applicable in the advanced stages of the disease and are associated with significant adverse effects.
The DR has traditionally been considered as a microcirculatory disease of the retina. However, as described in Lieth et al., Retinal neurodegeneration. Early pathology in diabetes, Clin. Exper. Ophthalmol., 2000, 28: 3-8, there is increasing evidence, based on neurophysiological, psychometric, histopathologic and biochemical observations, suggesting that retinal neurodegeneration is an early event in the pathogenesis of DR which participates in the microcirculatory abnormalities that occur in DR. Thus, the main features of retinal neurodegeneration (apoptosis and glial activation) have been detected in the retinas from diabetic donors who had no microvascular alterations. Clinically, retinal neurodegeneration produces functional abnormalities, such as loss of colour discrimination and of contrast sensitivity. These alterations can be detected in diabetic patients before injuries are observed in fundus examination.
In the review article Simó et al., Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives, Trends Endocrin. Metab., 2014, 25, 23-33, it is disclosed that treatments based on neuroprotection open a new approach to prevent or stop the development of DR. In this article some strategies are described which are in the experimental stage, but clinical trials supporting the efficacy and safety of these therapeutic approaches are not available yet.
In the article by Chou et al., Endothelin Receptor Antagonist-A Attenuates Retinal Vascular and neuroretinal Pathology in Diabetic Mice, Invest. Ophthalmol. Vis., 2014, 55, 2516-2525, oral administration of atrasentan, a selective blocking agent of ETA receptor of endothelin 1 is disclosed, and a significant reduction of vascular and neuroretinal complications in diabetic mice was observed. Such oral administration has the disadvantage that may have associated systemic effects. Furthermore, given the existence of the blood-retinal barrier, high serum concentrations are required for achieving pharmacological concentrations in the retina.
US 2003/0176356 describes a pharmaceutical composition comprising endothelin antagonists such as bosentan, but for treating a different disease, such as glaucoma. This document discloses general formulations which have not proven their viability. Indeed, they are applied generally stating that they can be used for any inhibitor of endothelin, when the galenical practice has shown that the same formulation developed for a particular active ingredient is not suitable for other active ingredient, albeit of the same drug family, because a small change in the molecular structure thereof presupposes the modification of its pharmaceutical, chemical and physical characteristics. In this case, it can be stated that the formulations set forth therein would not allow to obtain a stable solution and viable in time, without proving their correct preparation or their viability for ophthalmic application.
Despite the solutions described in the prior art, there is an ongoing need for new pharmacological therapies for the prevention and/or treatment of DR, which avoid the systemic treatment or intravitreal injections, in order to minimize potential side effects, and to be administered easily and over long periods.